Selection of patients suffering from hepatocellular carcinoma (HCC) in cirrhosis for liver transplantation follows limits of number and diameter of tumor nodules. It has not been investigated whether there is a correlation of these parameters with vascular invasion. From 1989 to 2000, 1,188 liver transplantations were performed in 1,087 patients, including 120 patients (11%) with an HCC in cirrhosis. Selection criteria were a maximal diameter of up to 5 cm if the tumor appeared to be uninodular or of up to 3 cm in the case of 2 or 3 nodules. The postoperative mortality rate was 1.7%. One-, 5-, and 10-year survival was 90%, 71%, and 60%, respectively. In 940 transplantation patients without an HCC, these rates were 93%, 87%, and 83% (P < .0001). Vascular invasion and histopathologic grading were identified as prognostic parameters by multivariate analysis. In a logistic regression analysis, histopathologic grading and maximal diameter showed a significant correlation with a vascular invasion. Analyzing tumors larger than 5 cm, i.e., tumors not fulfilling the selection criteria as a result of diagnostic inaccuracy or progression thereafter, the rates of vascular invasion were significantly (P < .01) lower in patients suffering from well-differentiated tumors ( De novo hepatocellular carcinoma (HCC) within cirrhotic livers or missed small satellites in patients undergoing formally curative liver resection have been reported to occur at a rate of 60%. 1 Most of these recurrent intrahepatic tumors were detected in a distance from the resection margin of at least 2 cm. However, only half of the patients with HCC in cirrhosis die from recurrence after resection, while the remaining half dies as a result of the underlying chronic liver disease. 2,3 Today, liver transplantation is the only simultaneous treatment of cirrhosis as well as of HCC. A crucial factor for outcome after liver transplantation is the appropriate selection of patients. TNM and UICC classification of HCC must be considered with caution for therapeutic decision making, because they comprise biologically different tumors in common categories, e.g., carcinomas with and without vascular invasion in T stages 2 to 4. 4 Bismuth et al. 5 were the first to show that in the early era of liver transplantation, the surgical strategy for the treatment of HCC in cirrhosis had followed a misconception in selecting patients suffering from advanced, and therefore unresectable, cancers, as transplant candidates. Conversely, small HCC in cirrhosis with diameters of less than 3 cm comprising only 1 or 2 nodules-tumors frequently suitable for resection-showed the most favorable outcome. Patients in whom the cancer has exceeded the hepatic confines should be ruled out for liver transplantation. Gross metastases or lymph node infiltration as indicators of an extrahepatic spread may easily be detectable pretransplantation by imaging procedures, laparoscopic staging, or intraoperatively. 6,7 However, the current state of pretransplantation and even intraoperative diagnostic ...

ObjectiveTo evaluate different strategies for extended resections of hilar cholangiocarcinomas on radicality and survival. Summary Background DataSurgical resection of hilar cholangiocarcinoma is the only potentially curative treatment. Resection of central bile duct carcinomas, however, cannot always comply with the general principles of surgical oncology to achieve wide tumor-free margins with no-touch techniques. MethodsFrom 1988 to 1998, 95 patients underwent resection of hilar cholangiocarcinoma. Eighty patients had hilar and hepatic resections and 15 had liver transplantation and partial pancreatoduodenectomy (LTPP; i.e., eradication of the entire biliary tract using a no-touch technique). ResultsThe 60-day death rate was 8%. The overall 1-and 5-year survival rates were 67% and 22%, respectively. Five-year survival rates after R0, R1, and R2 resections were 37%, 9%, and 0%. In a multivariate analysis, surgical radicality was the strongest determinant of survival (p Ͻ 0.001). The rate of formally curative resection (R0 resection) was significantly lower in hilar resections (29%) than in liver resections (left hemihepatectomy 59%, right hemihepatectomy 55%, right trisegmentectomy 65%; p Ͻ 0.05). The highest rate of R0 resection was observed after LTPP (93%; p Ͻ 0.05). Right trisegmentectomies achieved the highest rate of 5-year survival after R0 resection (57%). In a multivariate analysis of patient survival after R0 resection, additional portal vein resection was the only significant factor. The 5-year survival rate after formally curative liver resection with portal vein resection was 65% versus 28% without. ConclusionExtended resections, especially right trisegmentectomies and LTPP, resulted in the highest rate of R0 resection. Right trisegmentectomy together with portal vein resection best represents the principles of surgical oncology and may be regarded as the surgical procedure of choice. Immunosuppression limits the applicability of LTPP.Surgical strategies in the therapy of hilar cholangiocarcinoma afford patients the best chance for significant survival. Radical resections are currently considered as optimal treatment, but Ͻ20% of patients are estimated to be amenable to a formally curative approach.1,2 Local or hilar resections including the extrahepatic suprapancreatic biliary tract represent the least extensive resection procedures and have been shown to be safe, with a surgical death rate of Ͻ1% in selected series.3 In principle, patients with Bismuth-Corlette type I or type II tumors can undergo hilar resections with a curative intent. In practice, failure, even after formally curative extrahepatic bile duct resection, occurs in a high percentage of patients (76%) with locoregional recurrence. 4 Hilar cholangiocarcinomas involving either the right or left hepatic duct (Bismuth-Corlette types IIIa/IIIb) are generally proposed to require resection of the respective hemiliver to achieve clear margins. Recent studies on prognostic parameters after resection identified only tumor-free margins as a ...

In a prospective, multicenter, open-label study, de novo liver transplant patients were randomized at day 30±5 to (i) everolimus initiation with tacrolimus elimination (TAC Elimination) (ii) everolimus initiation with reduced-exposure tacrolimus (EVR+Reduced TAC) or (iii) standard-exposure tacrolimus (TAC Control). Randomization to TAC Elimination was terminated prematurely due to a higher rate of treated biopsy-proven acute rejection (tBPAR). EVR+Reduced TAC was noninferior to TAC Control for the primary efficacy endpoint (tBPAR, graft loss or death at 12 months posttransplantation): 6.7% versus 9.7% (−3.0%; 95% CI −8.7, 2.6%; p<0.001 for noninferiority [12% margin]). tBPAR occurred in 2.9% of EVR+Reduced TAC patients versus 7.0% of TAC Controls (p = 0.035). The change in adjusted estimated GFR from randomization to month 12 was superior with EVR+Reduced TAC versus TAC Control (difference 8.50 mL/min/1.73 m2, 97.5% CI 3.74, 13.27 mL/min/1.73 m2, p<0.001 for superiority). Drug discontinuation for adverse events occurred in 25.7% of EVR+Reduced TAC and 14.1% of TAC Controls (relative risk 1.82, 95% CI 1.25, 2.66). Relative risk of serious infections between the EVR+Reduced TAC group versus TAC Controls was 1.76 (95% CI 1.03, 3.00). Everolimus facilitates early tacrolimus minimization with comparable efficacy and superior renal function, compared to a standard tacrolimus exposure regimen 12 months after liver transplantation.

Bacterial infections frequently occur early after liver transplantation. We recently reported significant progress with a synbiotic composition, consisting of one lactic acid bacteria (LAB) and one fiber, which reduced the infection rate from 48% (with selective bowel decontamination) to 13%. Now, our aim is to study if a combination of different LAB and fibers would further improve outcome.A prospective randomized double-blind trial was undertaken in 66 liver transplant recipients. All patients received enteral nutrition immediately postoperatively. Comparison was made between one group (A) receiving a composition of four LAB and four fibers and another group (B) receiving the fibers only. The treatment started the day before surgery and continued for 14 days. Thirty-day infection rate, length of hospital stay, duration of antibiotic therapy, noninfectious complications and side effects of enteral nutrition were recorded.The incidence of post-operative bacterial infections was significantly reduced; being 48% with only fibers and 3% with LAB and fibers. In addition, the duration of antibiotic therapy was significantly shorter in the latter group. In both groups, mainly mild or moderate infections occurred. Fibers and LAB were well tolerated.Early enteral nutrition supplemented with a mixture of LAB and fibers reduces bacterial infection rates following liver transplantation. Treatment with only fibers led to a low incidence of severe infections.

In a 24‐month prospective, randomized, multicenter, open‐label study, de novo liver transplant patients were randomized at 30 days to everolimus (EVR) + Reduced tacrolimus (TAC; n = 245), TAC Control (n = 243) or TAC Elimination (n = 231). Randomization to TAC Elimination was stopped prematurely due to a significantly higher rate of treated biopsy‐proven acute rejection (tBPAR). The incidence of the primary efficacy endpoint, composite efficacy failure rate of tBPAR, graft loss or death postrandomization was similar with EVR + Reduced TAC (10.3%) or TAC Control (12.5%) at month 24 (difference −2.2%, 97.5% confidence interval [CI] −8.8%, 4.4%). BPAR was less frequent in the EVR + Reduced TAC group (6.1% vs. 13.3% in TAC Control, p = 0.010). Adjusted change in estimated glomerular filtration rate (eGFR) from randomization to month 24 was superior with EVR + Reduced TAC versus TAC Control: difference 6.7 mL/min/1.73 m2 (97.5% CI 1.9, 11.4 mL/min/1.73 m2, p = 0.002). Among patients who remained on treatment, mean (SD) eGFR at month 24 was 77.6 (26.5) mL/min/1.73 m2 in the EVR + Reduced TAC group and 66.1 (19.3) mL/min/1.73 m2 in the TAC Control group (p < 0.001). Study medication was discontinued due to adverse events in 28.6% of EVR + Reduced TAC and 18.2% of TAC Control patients. Early introduction of everolimus with reduced‐exposure tacrolimus at 1 month after liver transplantation provided a significant and clinically relevant benefit for renal function at 2 years posttransplant.

The majority of transplants are derived from donors who suffered from brain injury. There is evidence that brain death causes inflammatory changes in the donor. To define the impact of brain death, we evaluated the gene expression of cytokines in human brain dead and ideal living donors and compared these data to organ function following transplantation.Hepatic tissues from brain dead (n = 32) and living donors (n = 26) were collected at the time of donor laparotomy. Additional biopsies were performed before organ preservation, at the time of transplantation and one hour after reperfusion. Cytokines were assessed by real-time reverse transcriptase-polymerase chain reaction (RT-PCR) and cytometric bead array. Additionally, immunohistological analysis of tissue specimens was performed. Inflammatory cytokines including IL-6, IL-10, TNF-a , TGF-b and MIP-1a were significantly higher in brain dead donors immediately after laparotomy compared to living donors. Cellular infiltrates significantly increased in parallel to the soluble cytokines IL-6 and IL-10. Enhanced immune activation in brain dead donors was reflected by a deteriorated I/R injury proven by elevated alanin-aminotransferase (ALT), aspartat-amino-transferase (AST) and bilirubin levels, increased rates of acute rejection and primary nonfunction. Based on our clinical data, we demonstrate that brain death and the events that †Authors contributed equally to this manuscript.precede it are associated with a significant upregulation of inflammatory cytokines and lead to a worse ischemia/reperfusion injury after transplantation.

In patients with central bile duct carcinomas, hilar en bloc resection is oncologically superior to conventional major hepatectomy, providing a chance of long-term survival even in advanced tumors.

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